Germline hepatocyte nuclear factor 1α and 1β mutations in renal cell carcinomas

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Abstract
Mutations in one copy of the hepatocyte nuclear factors (HNF) 1α and 1β homeodomain containing transcription factors predispose the carrier to maturity-onset diabetes of the young (MODY) types 3 and 5, respectively. Moreover, previous identification of biallelic inactivation of HNF1α in hepatocellular adenoma identified its tumor suppressor function in hepatocarcinogenesis. The seminal observation of an ovarian carcinoma in a MODY5 patient who subsequently developed a chromophobe renal cell carcinoma, prompted us to screen for HNF1β and HNF1α inactivation in a series of 20 ovarian and 35 renal neoplasms. Biallelic HNF1β inactivation was found in two of 12 chromophobe renal carcinomas by association of a germline mutation and a somatic gene deletion. In these cases, the expression of PKHD1 (polycystic kidney and hepatic disease 1) and UMOD (Uromodulin), two genes regulated by HNF1β, was turned off. Interestingly, in two of 13 clear cell renal carcinomas, we found a monoallelic germline mutation of HNF1α with no associated suppression of target mRNA expression. In normal and tumor renal tissues, we showed the existence of a network of transcription factors differentially regulated in tumor subtypes. We identified two related clusters of co-regulated genes associating HNF1β , PKHD1 and UMOD in the first group and HNF1α , HNF4α , FABP1 and UGT2B7 in the second group. Finally, these results suggest that germline mutations of HNF1β and HNF1α may predispose to renal tumors. Furthermore, we suggest that HNF1β functions as a tumor suppressor gene in chromophobe renal cell carcinogenesis through a PKHD1 expression control.